title: Regulatory action of nitric oxide synthase on ileal P-glycoprotein expression under streptozotocin-induced diabetic condition.
abstract: P-glycoprotein (P-gp), a drug efflux transporter, affects the pharmacokinetics of a wide range of substrate drugs. Our previous study clearly revealed that intestinal P-gp expression levels were decreased via an inducible nitric oxide synthase (iNOS)-mediated mechanism in the early phases of diabetes. Here, we focused on changes in ileal P-gp expression and the influences of NOS on the P-gp expression levels in the later phase of diabetic condition using streptozotocin (STZ)-induced diabetic mice. The ileal P-gp expression and activity was analyzed by Western blot analysis and by in situ closed loop method, respectively. In STZ-treated mice, ileal P-gp expression levels and activity significantly decreased on the 9th day after STZ administration. Interestingly, the decrease of P-gp function was recovered to the control level on 15th day in same conditioned mice. In addition, the recovery of P-gp expression levels was completely suppressed by a non-selective NOS inhibitor. These results indicate that the diabetic condition-induced decline of P-gp expression levels was temporary, and both decline- and recovery-process of intestinal P-gp expression levels are mediated by NOS. Furthermore, this study shows the bidirectional effect of NOS on regulation of intestinal P-gp expression.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Kobe 650–8586, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Nawa
authors.forename: Wakako
authors.initials: W
authors.lastname: Fujita-Hamabe
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007082:Ileum / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D013311:Streptozocin / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D013311:Streptozocin; D019001:Nitric Oxide Synthase